Improved prediction of in vivo peroral absorption from in vitro intestinal permeability using an internal standard to control for intra- and inter-rat variability.
OBJECTIVE
To evaluate the use of an in vitro intestinal permeability model to predict rat and human absorption as well as to evaluate the use of an internal standard to control for intra- and inter-rat variability.


METHODS
In vivo peroral absorption and in vitro steady-state intestinal permeability coefficients were determined in the rat for a variety of structurally different compounds with different physicochemical properties including: progesterone, hydrocortisone, salicylic acid, caffeine, clonidine, p-aminoclonidine, UK-14304, oxymetazoline, mannitol, PEG 900, PEG 4000, and a number of novel hydrophilic chemical entities.


RESULTS
The intestinal permeability coefficients determined in vitro could be used to predict the peroral absorption of a compound in both the rat and human. Normalizing the permeability of a test compound to an internal standard, e.g. mannitol, greatly improved the prediction of peroral absorption.


CONCLUSIONS
The use of an internal standard can aid in the prediction of the peroral absorption of a test compound, in particular, for one that has moderate absorption in the range of 20-80%. Moreover, these methods would appear to be a useful means to improve the prediction of other absorption models as well, such as the Caco-2 cell systems and in-situ perfusion methods.
Dowty
M E
ME
Procter and Gamble Pharmaceuticals, Health Care Research Center Mason, Ohio 45040, USA. dowtyme@pg.com
Dietsch
C R
CR
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D018938:Caco-2 Cells; D006801:Humans; D007082:Ileum / Q000378:metabolism*; D007408:Intestinal Absorption / Q000502:physiology*; D008297:Male; D008353:Mannitol / Q000592:standards; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012015:Reference Standards; D013045:Species Specificity; D013329:Structure-Activity Relationship
D004364:Pharmaceutical Preparations; D008353:Mannitol